Sunday, 19 October 2014

OffLabel: cladribine

Cladribine is my fourth off label DMT for treating MS in resource poor environments. #MSBlog #MSResearch #OffLabel

"This post is the fourth in a series of posts to try and help neurologists who treat MS in healthcare environments where they cannot access high-cost innovator DMTs. If you want to know the history of this post please read my post on my visit to South Africa. The other three off-label DMTs are methotrexate, azathioprine and mitoxantrone."

"Many of you will know that oral cladribine got through the development pipeline and was licensed in Russia and Australia before Merck-Serono decided to pull the plug on the drug and withdraw it from all markets. The reason for doing this was complex, but both the EMA and FDA wanted more safety data after the seeing only one phase 3 pivotal study (CLARITY Study, study 1 below). This decision was made before the second phase 3 study in CIS (ORACLE Study, study 2 below) was completed. An apparent signal of secondary malignancies emerged in this first study that was not seen in the second study. I was particularly disappointed with Merck-Serono's decision to pull cladribine, particularly in view of the extraordinary results of the CIS study and the observation that secondary malignancies were not a problem in the second study. This does not mean there the secondary malignancy issue has gone away, however, it is likely to be a small problem similar to that seen with other immunosuppressive drugs. Please note that one of the functions of the immune system is to fight malignancies and when you suppress the immune system you get a higher incidence of secondary malignancies; these tend to come on many years later and predominated by lymphomas and skin cancers. The only way you will find out about the risk of secondary malignancies is via so called post-marketing surveillance studies or registers and not in phase 3 studies. Hence why it is difficult to accept the FDA's and EMA's reasoning."

"We don't have oral cladribine, but that doesn't mean to say you can't use it. What we are suggesting is going back to the subcutaneous formulation that is licensed for treating hairy cell leukaemia. I have uploaded the Royal London Hospital's protocol for your information. We tend to use it patients with relapsing secondary-progressive disease who have failed other therapies, for whom we don't have a licensed therapy. However, in resource poor countries and environments where you can't access licensed DMTs I would use it in active MSers as a first, second or third line therapy. It is clear from the CIS or ORACLE study that the sooner you use cladribine the better the outcome. The main safety signal is infection, particularly herpes infections and low white blood counts. For the herpes infections you need to be vigilant and treat them with anti-virals. In subjects who are seronegative for VZV (varicella-zoster virus) they should be vaccinated against the virus before starting cladribine. In countries with a high background rate of tuberculosis it is important to screen for, and exlcude ative or latent, TB infection. The lymphopaenia (low lymphocyte counts) can be managed by strict redosing guidelines. Please note I would suggest using cladribine as we use alemtuzumab, i.e. as an induction agent. I would only give two years of treatment and then monitor to see if there is any breakthrough disease before administering further courses."

Study1: Giovannoni et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med. 2010 Feb 4;362(5):416-26.

BACKGROUND: Cladribine provides immunomodulation through selective targeting of lymphocyte subtypes. We report the results of a 96-week phase 3 trial of a short-course oral tablet therapy in patients with relapsing-remitting multiple sclerosis.

METHODS: We randomly assigned 1326 patients in an approximate 1:1:1 ratio to receive one of two cumulative doses of cladribine tablets (either 3.5 mg or 5.25 mg per kilogram of body weight) or matching placebo, given in two or four short courses for the first 48 weeks, then in two short courses starting at week 48 and week 52 (for a total of 8 to 20 days per year). The primary end point was the rate of relapse at 96 weeks.

RESULTS: Among patients who received cladribine tablets (either 3.5 mg or 5.25 mg per kilogram), there was a significantly lower annualized rate of relapse than in the placebo group (0.14 and 0.15, respectively, vs. 0.33; P<0.001 for both comparisons), a higher relapse-free rate (79.7% and 78.9%, respectively, vs. 60.9%; P<0.001 for both comparisons), a lower risk of 3-month sustained progression of disability (hazard ratio for the 3.5-mg group, 0.67; 95% confidence interval [CI], 0.48 to 0.93; P=0.02; and hazard ratio for the 5.25-mg group, 0.69; 95% CI, 0.49 to 0.96; P=0.03), and significant reductions in the brain lesion count on magnetic resonance imaging (MRI) (P<0.001 for all comparisons). Adverse events that were more frequent in the cladribine groups included lymphocytopenia (21.6% in the 3.5-mg group and 31.5% in the 5.25-mg group, vs. 1.8%) and herpes zoster (8 patients and 12 patients, respectively, vs. no patients).

CONCLUSIONS: Treatment with cladribine tablets significantly reduced relapse rates, the risk of disability progression, and MRI measures of disease activity at 96 weeks. The benefits need to be weighed against the risks. ( number, NCT00213135.)

Study 2: Leist et al. Effect of oral cladribine on time to conversion to clinically definite multiple sclerosis in patients with a first demyelinating event (ORACLE MS): a phase 3 randomised trial. Lancet Neurol. 2014 Mar;13(3):257-67.

BACKGROUND: Patients who develop relapsing-remitting multiple sclerosis (MS) present with a first clinical demyelinating event. In this double-blind, multicentre, randomised, phase 3 study we investigated the effect of oral cladribine on conversion to clinically definite MS in patients with a first clinical demyelinating event, when given at the same doses shown to be effective in relapsing-remitting MS.

METHODS: Between Oct 21, 2008, and Oct 11, 2010, we recruited patients aged 18-55 years, inclusive, from 160 hospitals, private clinics, or treatment centres in 34 countries. Eligible patients had a first clinical demyelinating event within 75 days before screening, at least two clinically silent lesions of at least 3 mm on a T2-weighted brain MRI scan, and an Expanded Disability Status Scale score of 5.0 or lower. Patients with a first clinical demyelinating event ≤75 days before screening were randomly assigned (1:1:1) to receive cladribine tablets at cumulative doses of 5.25 mg/kg or 3.5 mg/kg or placebo. Randomisation was done with a central web-based randomisation system and was stratified by geographic region. Masking was maintained using a two-physician model. The primary endpoint of this 96-week study was time to conversion to clinically definite MS according to the Poser criteria. This study is registered with, number NCT00725985.

FINDINGS: Of 903 participants assessed for eligibility, 616 patients received cladribine 5.25 mg/kg (n=204), cladribine 3.5 mg/kg (n=206), or placebo (n=206). At trial termination on Oct 25, 2011, cladribine was associated with a risk reduction versus placebo for time to conversion to clinically definite MS (hazard ratio [HR] for 5.25 mg/kg=0.38, 95% CI 0.25-0.58, p<0.0001; HR for 3.5 mg/kg=0.33, 0.21-0.51, p<0.0001). Adverse events were reported in 165 (81%) patients in the cladribine 5.25 mg/kg group, 168 (82%) patients in the cladribine 3.5 mg/kg group, and 162 (79%) patients in the placebo group. We noted no increase in risk of adverse events with active treatment versus placebo apart from lymphopenia, which was a severe event in 10 (5%) patients in the 5.25 mg/kg group and four (2%) patients in the 3.5 mg/kg group.

INTERPRETATION: Both doses of cladribine significantly delayed MS diagnosis compared with placebo. The safety profile of cladribine was similar to that noted in a trial in patients with relapsing-remitting MS. Further research could clarify the potential effects of oral cladribine treatment in the early stages of MS.

Study 3: Beutler et al. The treatment of chronic progressive multiple sclerosis with cladribine. Proc Natl Acad Sci U S A. 1996 Feb 20;93(4):1716-20.

A 2-year, placebo-controlled, double-blind, crossover study was started in 1992 to evaluate cladribine, an immunosuppressive drug, in the treatment of chronic progressive multiple sclerosis. In the first year patients were given cladribine 0.10 mg/kg per day for 7 days as four monthly courses for a total of 2.8 mg/kg or placebo. During the second year patients treated with placebo during the first year were given i.v. infusions of 0.10 mg, 0.05 mg, and 0.05 mg of cladribine per kg of body weight per day for 7 consecutive days in three successive monthly courses, for a total dose of 1.4 mg/kg. Patients who had been treated previously with cladribine were crossed over to placebo. Analysis of the results revealed a favorable influence on the neurological performance scores, both in the Kurtze extended disability status and the Scripps neurological rating scale, and on MRI findings in patients treated with cladribine. In the first year the most striking finding was that while clinical deterioration continued in the placebo-treated patients, the condition of patients who received cladribine stabilized or even improved slightly. Toxicity and therapeutic response were dose-related.

Study 4: Sipe et al. Cladribine in treatment of chronic progressive multiple sclerosis. Lancet. 1994 Jul 2;344(8914):9-13.

Chronic progressive multiple sclerosis (MS) is a severely disabling demyelinating disease in which autoimmune processes seem to have a major role. The nucleoside drug cladribine is a potent lympholytic agent with few side-effects. We have studied its efficacy and safety in a randomised double-blind trial. 51 patients (48 entered as matched pairs) received four monthly courses of 0.7 mg/kg cladribine or placebo (saline) given through a surgically implanted central line. Neurologists with no knowledge of which medication the patient was receiving examined the patients monthly and noted two rating scale scores (Kurtzke and Scripps). Cerebrospinal fluid and brain magnetic resonance imaging (MRI) examinations were done at 6 and 12 months. Average neurological scores, demyelinated volumes on MRI, and concentrations of oligoclonal bands in cerebrospinal fluid were stable or improved in the patients receiving cladrabine but continued to deteriorate in patients on placebo. Mean paired (placebo minus matched cladribine) differences at 12 months relative to baseline were 1.0 (SE 0.4) for the Kurtzke scores, -13.9 (2.3) for the Scripps scores, 4.57 (1.17) mL for demyelinated volumes, and 7.3 (3.3) arbitrary units for concentrations of oligoclonal bands. Cladribine was generally well tolerated and clinically significant toxicity occurred in only 1 patient, in whom severe marrow suppression developed with complete recovery after several months. 1 patient died of newly acquired hepatitis B, an event unlikely to be related to cladribine. We conclude that the immunosuppressive drug cladribine influences favourably the course of chronic progressive MS.

CoI: multiple


  1. Why is Cladribine 4th in the list and not 1st?
    It has been through phase 3 trials and could easily have been one an approved induction agent DMT along with alemtuzumab

    1. Re: "Why is Cladribine 4th in the list and not 1st?"

      No specific order; the order they come in is not their rank. I agree cladribine should probably be ranked first in terms of the level of evidence next to its name.

  2. Prof G surely you need to include leflunomide on the essential list? This is essentially a pro-drug for teriflunomide that is now licensed across the world.

  3. In how many patients have you used cladribine off-label in at your hospital?

    1. Re: "In how many patients have you used cladribine off-label in at your hospital?"

      We haven't yet but need a drug in reserve for patients with active MS who aren't eligible for DMTs under NICE/NHS England guidelines and don't want to take mitoxantrone because of its safety profile. This is now more acute since NHS England have blocked individual funding requests for off-label use of rituximab.

      Please note that in Europe we are not allowed to prescribe and off-label drug when there is a licensed therapy for that indication. This means that we can't use any of the DMTs on this list, with the exception of mitoxantrone that is licensed in several EU member states. I think the legislation behind this is correct in that it protects Pharma's investment in the field of MS.

    2. Does this mean that the extensive open-label use of alemtuzumab in several UK centers prior to Lemtrada's license was illegal?

    3. The essential DMT list is not for the EU or other developed markets; it is simply my attempt to help treat MS in resource poor settings, where high-cost licensed drugs are not available. If I recall correctly all the patients treated in Cambridge were part of a clinical trial and once the phase 3 programme started they stopped all off-label prescribing. I can't speak for the other sites in the UK.

      If you are interested we have been through the issues around off-label prescribing in the NHS many times on this blog. I would urge you to read the following posts:

  4. Do you have many people coming to you to have IV cladribine therapy? I am in NZ where no neurologist is keen to prescribe or administer this protocol, would it be possible to self-fund this in the UK?


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